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Query: UNIPROT:P06889 (Mol)
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Single cardiac myocytes were isolated from the ventricles of failing and non-failing human hearts. The contraction amplitude, time-to-peak shortening and time to 50% and 90% relaxation were measured in cells stimulated at 0.2 Hz at 32 degrees C. The effects of increasing extracellular calcium and isoproterenol were investigated using cumulative concentration/response curves. Maximum contraction amplitude in high calcium or velocities of contraction or relaxation were not impaired in cells from failing hearts. Beta-adrenoceptor function in a single cell was assessed by the maximum contraction amplitude in the presence of isoproterenol relative to that with high calcium in the same cell (isoproterenol/calcium ratio). A decrease in the isoproterenol/calcium ratio correlated positively with an increase in the isoproterenol EC50 (concentration for half-maximal effect) for a cell (P less than 0.02, n = 39). The isoproterenol/calcium ratio in left ventricular myocytes decreased with increasing severity of disease, correlating with failure as defined by New York Heart Association class (P less than 0.001, n = 26 patients), left ventricular ejection fraction (P less than 0.001, n = 24), left ventricular end diastolic pressure (P less than 0.05, n = 21) and amount of diuretics prescribed (P less than 0.001, n = 26). In right ventricular myocytes, only increasing NYHA class correlated with decreasing isoproterenol/calcium ratios. There was a correlation of the isoproterenol/calcium ratio between right and left ventricular cells from patients with ischemic heart disease (P less than 0.05), n = 11). Beta-adrenoceptor subsensitivity occurred in mitral valve disease, ischemic heart disease, congenital abnormalities and congestive cardiomyopathy, but not in the right ventricle of patients with myocarditis. The isoproterenol/calcium ratio correlated negatively with the age of the patient (P less than 0.001, n = 26, left ventricle). Multiple regression indicated that the maximum contraction amplitudes in either high isoproterenol or high calcium declined significantly with age only, but that both age and severity of disease contributed to the decrease in isoproterenol/calcium ratio. Time-to-peak tension in isoproterenol, as well as relaxation times in high calcium also decreased with the age of the patient. Analysis of variance showed that between-patient variation was significantly greater than between-cell for most of the parameters measured. Beta-adrenoceptor desensitisation may be detected in individual myocytes from failing hearts, and this relates more to the severity of disease and the age of the patient rather than the etiology of heart failure. A decline in absolute contractility of muscle cells with age was detected.
J Mol Cell Cardiol 1992 May
PMID:Isolated ventricular myocytes from failing and non-failing human heart; the relation of age and clinical status of patients to isoproterenol response. 132 14

T lymphocytes from T. cruzi infected mice susceptible to the development of myocarditis altered the contractility of normal mouse atria in vitro. While lymphocytes obtained from normal mice had no effect, lymphocytes from T. cruzi-infected mice cultured with normal atria induced negative or positive inotropic effects depending upon the post-infection period; negative inotropism was induced by lymphocytes obtained from animals at 1 to 4 weeks post-infection, and positive inotropism was induced by lymphocytes taken at 7 to 14 weeks post-infection. These effects were mediated by soluble factors as evidenced by the ability of lymphocyte culture supernatants to alter contractility. Cell enrichment experiments indicated that T lymphocytes rather than B lymphocytes were responsible for these inotropic effects. Lyt(2+)-enriched T lymphocytes were found to be responsible for triggering the negative inotropic effect at 3 weeks post-infection when myocarditis was less intense, whereas Lyt1(+)-enriched T lymphocytes induced the positive inotropic effect at 8 weeks after T. cruzi infection when myocarditis was severe. Furthermore, inhibitors of the cyclooxygenase pathway of arachidonic acid metabolism blunted the negative inotropic effect while inhibitors of lipoxygenase pathway inhibited the positive inotropic effect. PGE2 was found to be spontaneously released by Lyt(2+)-enriched T cells obtained at 3 weeks post-infection while LTC4 was released by atria cultured in the presence of Lyt 1+ T cells obtained at 8 weeks post-infection. In conclusion, these findings suggest that infiltrating T lymphocytes may contribute to myocardial dysfunction during T. cruzi infection by releasing or inducing the release of harmful arachidonic acid metabolites such as PGE2 and LTC4 which alter normal cardiac function.
J Mol Cell Cardiol 1992 Jan
PMID:T lymphocytes from T. cruzi-infected mice alter heart contractility: participation of arachidonic acid metabolites. 156 33

Murine coxsackie B virus infection models of myocarditis and numerous human serologic studies associating elevated enterovirus-specific IgM titers with the clinical diagnosis of myocarditis have been used to support an etiologic role for enteroviruses in human myocarditis. Of the human enteroviruses, coxsackie B viruses (CVB) are the enterovirus group most commonly associated with the human disease. While hybridization probes exist to detect most, if not all, human enteroviruses, no probe capable of specifically detecting an enteroviral group (such as the CVB) to the exclusion of all others has been described to date. Thus, to test the hypothesis that enteroviral involvement in human myocarditis is commonplace, we examined a case series of human myocarditic heart tissues for enteroviruses by in situ hybridization using a generic enterovirus probe. These results were then compared with CVB-specific IgM levels in the cognate patient sera. Comparison of the hybridization data with the CVB-specific IgM levels in the cognate sera yielded no valid correlation between the detection of enteroviral RNA and specificity of CVB identification in any patient. The data are consistent with common enterovirus infections in humans and a possible etiologic role in myocarditis but do not support a specific etiologic role for CVB in this study group.
J Mol Cell Cardiol 1990 Apr
PMID:A molecular and serologic evaluation of enteroviral involvement in human myocarditis. 216 82

The presence of viral genomes in the murine heart in experimental coxsackievirus B3 myocarditis was investigated by Northern blotting analysis. Four-week-old C3H/He mice were inoculated with coxsackievirus B3. After sacrifice, the hearts were divided into 3 parts. Total RNA was extracted from one part of the heart. The other two parts were used for investigation of histopathology and of virus titer by plaque assay. The 32P-labeled cDNA probe was derived from the 5' end sequence of the coxsackievirus B3 genome. Northern blot autoradiograms of heart RNA were positive for viral RNA until day 7 and negative after day 10 and in control (uninfected) hearts. Positive autoradiograms always had the strongest signal at about 7.4 kilobase, corresponding to the size of the complete genome of the virus. The viral genomes were detected earlier than the appearance of the histopathologic changes in the murine heart. This type analysis of the viral genome in the murine myocardium may be useful in evaluating the effects of specific drugs on experimental viral myocarditis at the level of the viral genome.
J Mol Cell Cardiol 1990 Sep
PMID:The viral genome in experimental murine Coxsackievirus B3 myocarditis: a Northern blotting analysis. 217 95

Human picornaviruses include rhinoviruses and enteroviruses which are responsible for both common and severe clinical diseases. Rhinoviruses are a frequent cause of respiratory infections while members of enterovirus subgroups, polio, coxsackie and ECHO viruses are often responsible for infections of the central nervous system, myocarditis, myositis etc. Human picornaviruses consist of nearly two hundred serotypes and therefore their specific identification after virus isolation, or the diagnosis based on the detection of immune response in patients, is problematic and does not usually provide virological diagnosis at the acute phase of illness. New methods for detection of picornavirus genomic RNA together with increasing knowledge of the nucleotide sequences of this virus group offer interesting possibilities for diagnostic procedures. Spot hybridization, in situ hybridization and enzymatic amplification of specific sequences have successfully been used for this purpose. Probes covering the 5' non-coding part of the genome, and also sequences derived from the region coding for non-structural proteins, can be used as broadly reacting reagents in picornavirus detection. Specific sequences are mainly found in the capsid protein region of the genome. cDNA probes and synthetic oligonucleotides are useful in rapid identification of picornaviruses after amplification in cell cultures and in epidemiological analysis. The biochemical amplification methods may enable recognition of picornaviruses directly in clinical samples in the near future. In situ hybridization methods have been of special interest because they can be used to reveal the presence of enterovirus genomes in biopsy specimens from e.g. affected heart muscle in patients with myocarditis and cardiomyopathy.
Mol Cell Probes 1989 Dec
PMID:Identification of human picornaviruses by nucleic acid probes. 255 19

Reovirus is a double-stranded RNA-virus which induces myocarditis in newborn mice. Due to the large diameter of the viral particles (70-75 nm) it can be detected by electron microscopy. Subcutaneous inoculation of 0.05 ml reovirus type 3 (TCID50-titer: 10(8.5)/ml) into newborn NMRI-mice (12-18 h after birth) caused a grey-yellow mottling on the ventricular surface first seen on the 5th day after birth. At the same time muscle fiber necrosis was observed which increased with time. Electron microscopic investigations of the diseased heart muscle disclosed a marked interstitial oedema, swelling of the tubular system and sarcoplasmic reticulum, and degenerative changes in the mitochondria of individual myocardiocytes as early as the 2nd post-inoculation day. Simultaneously, an enlarged Golgi-apparatus and an increasing number of lysosomes, partially exhibiting acid phosphatase activity, was detected in the perinuclear region of ventricular myocardiocytes. On the 5th day after infection, viruses were detected either within single membrane vesicles, dispersed in cytoplasm or as aggregated clusters in the perinuclear region. These in vivo electron microscopic findings correspond with observations of virus propagation in cell-culture systems.
Virchows Arch B Cell Pathol Incl Mol Pathol 1986
PMID:Experimental reovirus myocarditis in newborn mice. Electron microscopic observations. 287 May 87

In most patients with virus myocarditis, the diagnosis is still based on clinical data alone. Endomyocardial biopsies subjected to electron microscopy, immunofluorescence techniques and virus isolation procedures provide additional, but only occasionally conclusive information. In this communication we describe a new method which could possibly be used to improve the diagnostic possibilities in patients with suspected virus myocarditis. The method is based on the hybridization of radioactive complementary nucleotide sequences to virus-RNA. It is shown that in an experimental model (reovirus infected baby mice) this method can be used to demonstrate the virus infection of cardiac muscle. It is suggested that the method could be adapted to other viruses (e.g. coxsackie virus) and to endomyocardial biopsies derived from patients with suspected virus myocarditis.
J Mol Cell Cardiol 1985 Jan
PMID:Virus myocarditis: molecular hybridization allows the detection of virus-RNA in heart muscle after virus infection. 298 89

Methods for evaluating cardiac myocyte necrosis utilizing antibodies specific for the heavy or light chains of cardiac myosin are reviewed. Cell death, associated with sarcolemmal disruption, results in the leakage of myosin light chains from the cytoplasm as well as the accessibility of myosin heavy chains to exogenous specific antibodies. Measurement of plasma light chain concentration has been useful in the diagnosis of myocardial infarction, though more recently, patients with congestive cardiomyopathy associated with an inflammatory infiltrate have been identified by an elevated plasma light chain concentration. The binding of myosin heavy chains to necrotic myocytes has been useful in the study of mechanisms of ischemic cell death in cell culture, in the diagnosis and quantification of myocardial infarction, both experimentally and clinically, and more recently in the study of experimental myocarditis and cardiac transplantation. It is hoped that these methods may evolve as useful clinical tools in the identification of those cardiomyopathy patients whose course is characterized by rapid myocyte loss.
J Mol Cell Cardiol 1985 Jul
PMID:Quantifying cell death in the myocardium: myosin specific antibody in the evaluation of membrane defects. 299 33

Anti-virus-antibodies are elevated in a relatively high number of dilated cardiomyopathies, and in myocarditis increasing or decreasing titers can characteristically be observed. In myocarditis as well as in dilated cardiomyopathy the high incidence of antibodies in the serum of the patients against myocardial sarcolemmal and mitochondrial proteins coincides with a low T-cell-suppressor activity. T-lymphocyte-cell-suppressor activity modifies the immunoglobulin synthesis of B-lymphocytes. The T-cell-suppressor activity has been found to be low in myocarditis as well as in congestive cardiomyopathies. This coincidence looks like a pathogenetic link, since a low T-cell-suppressor activity is generally correlated to an increased antibody synthesis of B-lymphocytes. The finding of a low T-cell-suppressor activity in a small group of normal individuals supports the concept that this group has a predisposition to suffer from myocarditis and later on developing dilated cardiomyopathy. Thus there are several indicators of a probably genetically determined immunological defects which can play a pathogenetic role in the development from myocarditis to dilated cardiomyopathy.
J Mol Cell Cardiol 1985 Jul
PMID:Immunological defects precursors of myocarditis and dilated cardiomyopathy? 316 35

In this paper it was examined whether it could reproduce "in vitro", some of the myocardial dysfunction see "in vivo" in autoimmune myocarditis. The isolated atria from mice hyperimmunized with heart exhibited a lymphomononuclear cell infiltration and alteration in contractility: dysrhythmia and decrease in tension. These alterations highly resembled that triggered by spleen lymphocytes from autoimmune myocarditis mice, when they reacted with normal atria. This effect appears to be specific since cells sensitized to an irrelevant antigen were inactive, and was not secondary to allogenic interaction. The free-cell supernatant of autoimmune cells was inactive, point out the requirement of lymphocyte-heart contact. The most likely effectors of lymphocytes-induced alteration of atria contractility were T-lymphocytes. Beta-lymphocyte subset had no effect. Inhibitors of lipoxygenase(s) pathway of arachidonic acid metabolism, inhibited induced alterations of contractility and the SRS-A receptor blocker, FPL-55712 improved cardiac function. In addition LTC4 release was increased either in autoimmune myocarditis hearts and in normal hearts challenged with autoimmune cells; the hearts proving to be responsible of leukotriene synthesis. Normal or immune cells alone failed to release LTC4. Lipoxygenase(s) inhibitors diminished LTC4 release while indomethacin could not reverse the effect. It is concluded that mononuclear cells infiltrates occurring in hearts with autoimmune myocarditis mice are related to cardiac impairment, being critical in the myocardial dysfunction etiology. The way suggested for these phenomena to take place is, at least in part, the harmful effect of SRS-A released by hearts when specific antigens of myocardial tissue are recognized by autoimmune cells.
J Mol Cell Cardiol 1988 Feb
PMID:Lymphocytes infiltration induces dysfunction in autoimmune myocarditis: role of SRS-A. 326 Sep 62


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